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Caspases in olfactory neuron aptosis Cowan, Catherine M.


The process of neuronal apoptosis is essential in brain development, and is an important component of many neurodegenerative diseases. Protease enzymes of the caspase family are key elements in the molecular events occurring during apoptosis. The combination of caspases utilized depends upon the death stimulus and cell type. Caspases-3 and -9 have been implicated in developmental neuronal apoptosis, as both caspase-3 and caspase-9 null mice display attenuated apoptosis during embryonic development resulting in excess neurons. The olfactory system (OS) is an excellent system for studying apoptosis of mature neurons in vivo, because the mature olfactory receptor neurons (ORNs) are physically distinct from other neuronal populations, are easily manipulated, and project to one target, the olfactory bulb. I show that ORNs undergoing apoptosis after removal of the olfactory bulb, undergo a retrograde wave of activation of caspase-9 and caspase-3, proceeding from synapse to cell body. This is the first time such a wave has been demonstrated in any neuronal system. Caspase-3 null mice demonstrate that caspase-3 is required for acute bulbectomy-induced apoptosis. Nothing was previously known about the role of any apoptotic molecules in OS development. I show that caspase-3 is necessary for correct OS development: caspase-3 null adult mice have OS abnormalities including an expanded ORN population, and post-natal onset olfactory bulb abnormalities. An expanded olfactory epithelium (OE) is evident as early as embryonic day (E)13 in caspase-3 and caspase-9 nulls, coinciding with wildtype peak of OE apoptosis and onset of OE caspase-3 expression. OE apoptosis is decreased five-fold at E13 in caspase-3 and caspase-9 nulls, but normal low levels are seen postnatally. Caspase-3 and -9 are crucial for E13-specific presynaptic wave of developmental death, the absence of which results in life-long neuronal abnormalities. However, ORNs can utilize a caspase-3/9-independent death mechanism depending upon maturational state and possibly signals received. Taken together, these results suggest that neurons at different stages of the same lineage can die by different mechanisms.

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